Method of treating nematode infestations

ABSTRACT

A method of eliminating parasitic nematodes inhabiting a mammal which comprises orally administering to said mammal a nematocidally effective amount of a compound of the Formula I   in the above formula R&#39;&#39; is lower alkyl, NR2 is diloweralkylamino or pyrrolidino, Z is p-halogenophenyl, p-lower alkoxy phenyl, pphenoxy phenyl, p-biphenylyl, phenyl, p&#39;&#39;-lower alkoxy-pbiphenylyl or Beta -napthyl and X is an anion of a pharmaceutically acceptable acid. Composition including the compound of the above Formula I are suitable for oral administration.

United States Patent [1 Phillips et al.

[451 May 13,1975

[ METHOD OF TREATING NEMATODE INFESTATIONS [75] Inventors: Arthur P. Phillips, Raleigh; Robert B. Burrows, Cary, both of NC.

[73] Assignee: Burroughs Wellcome Co., Research Triangle Park, NC.

[22] Filed: May 24, 1971 [21] Appl. No.: 146,549

Related U.S. Application Data [63] Continuation-impart of Ser. No. 760.966, Sept. 19, 1968, Pat. No. 3,641,012. and a continuation-in-part of Ser. No. 760,965, Sept, 19, 1968, abandoned.

OTHER PUBLICATIONS Sych. Ukrain. Khim. Zhur., 24, 79-88, (1958) (same as CA. 52; 18377bl8378d). Remingtons Pharmaceutical Sciences, 13 ed., p. 566, (1965).

Venkataroman, The Chemistry of Synthetic Dyes," Vol. 11, pp. 1185-1186, (1952).

Primary Examiner-Albert T. Meyers Assistant Examiner-Leonard Schenkman Attorney, Agent, or Firm-Dike, Bronstein, Roberts, Cushman & Pfund [57] ABSTRACT A method of eliminating parasitic nematodes inhabiting a mammal which comprises orally administering to said mammal a nematocidally effective amount of a compound of the Formula 1 in the above formula R is lower alkyl, NR is diloweralkylamino or pyrrolidino, Z is p-halogenophenyl, plower alkoxy phenyl, p-phenoxy phenyl, p-biphenylyl, phenyl, p'-lower alkoxy-p-biphenylyl or B-napthyl and X" is an anion of a pharmaceutically acceptable acid. Composition including the compound of the above Formula I are suitable for oral administration.

43 Claims, No Drawings 1 2 METHOD OF TREATING NEMATODE wherein NR is diloweralkylamino, where the alkyl is INFESTATIONS methyl, ethyl or propyl, and is preferably dimethylamino, diethyl amino or is pyrrolidino, R' is methyl,

This application is a continuation-in-part of U.S. Pat. ethyl, propyl and is preferably methyl or ethyl and Z is application Ser. No. 760,966 filed Sept. 19, 1968, now s l cte from h cl ss con isting of phenyl, p- U.S. Pat. No. 3,64l ,012 and US. Pat. application Ser. halogenophenyl, preferably p-bromophenyl or p- No. 760,965 filed Sept. 19, 1968, now abandoned. chlorophenyl, p-loweralko y (l o 3 carbons) ph nyl.

The present invention is directed to a method of pref rably p-m hoxyph nyl, p-phen xyphenyl. peliminating nematodes, i.e., pinworms, hookworms, p y y PlOWGYalKOXY t0 3 Carbfln atoms) p whipworms and other types inhabiting a mammal pary y that is P'- y-pp y y Sometimes ticularly the intestinal tract thereof by administering an ritte as p-p' biphenylyl lower alkoxy or p-p'- effective amount of a 2-(p-tertiary aminostyryl) e t e t lOWBYalkOXY Preferably P'- y-P- thiazolium salt. In this invention, the preferred effecp y yuP-P'- e 4 s 4 a) and p y P tive amount for a single dose is 5-25 mg of cation lkg ably B-naphthyl and X is the anion of a pharmaceutiof body weight of the mammal being treated. cally acceptable acid and is one that is not itself mark- Tests have shown that the method of treatment of edly toxic. Of the compounds of this invention the folthis invention is effective against Ancylosroma canium lowing styryl thiazolium salts of the Formulas IA or 1B (of dogs), Ancylostoma tubaeforme (of cats), Toxocara having a substituent Z that are p-biphenylyl or canis (of dogs), Trichuris vulpis (in dogs), Syphacia obp'-loweralkoxy-p-biphenylyl are particularly useful in velata (in mice), Nippostrongylus brasiliensis (in rats). treating nematode infestations.

5 Y I {k en-011% !|(n) All of these parasites except the last two are ofinherent where Y is hydrogen or lower alkoxy (methoxy, ethoxy, practical interest. Syphacia obvelata is a pinworm of propoxy, etc.), X is an anion of a pharmaceutically acmice which has been widely considered to be a reliable ceptable acid R is lower alkyl (methyl, ethyl, propyl, guide in the discovery of compounds active against Enetc.) and ---s ooterobius vermicularis, the pinworm of man. These comwhere Y is hydrogen or lower alkoxy, (methoxy, ethpounds are represented generally by Formula I oxy, propoxy, etc.) X is an anion of a pharmaceutically acceptable acid, and R is lower alkyl. 3

H GH NR Especially preferred are the variants II, which has been shown to eliminate hookworms from dogs (Amy- 2 losmma caninum and Uncinaria srenocephala) and cats I (Ancylostoma tubaeforme) at doses of Srng/kg and has an,oral LD (in mice) of l650mg/kg.

CH3 xand III which is highly active against pinworms. In the above E, is the well known abbreviation for ethyl or C l-I Considerable variation in activity against different parasites exists within this series. In general, maximal activity against hookworms in the Formula I is found with R=R'=methyl. Activity against Syphacia obvelata is highest when R is ethyl and NR, is pyrrolidino. All of the compounds of Examples 1-25 however, eliminate hookworrns from dogs at doses of the order of 25mg base/kg or clear mice of Syphacia at doses of 100mg base /kg or less.

Compounds of Examples 4, 5, 9 and 10 have been reported previously (Chem. Abs.,l7, l024'(l923), 40, 1519*(1946), 52, 18377 (l958),l8,264(l924) re- Conveniently, however, X is introduced in step c through the alkylating agent R'X which, to prepare 1], would be methyl iodide or methyl sulfate. The most conveniently prepared salts of ll are thus the iodide and methyl sulfate. lf methyl bromide were employed in step c, the bromide of II would result. The chloride can be prepared from the iodide by shaking with silver chloride in alcoholic solution and other salts by appropriate conventional procedures.

The compounds of the present invention are conveniently prepared as more particularly shown for Y= lower alkoxy or hydrogen, R is lower alkyl, and NR is dialkylamino or pyrrolidino by the following reaction sequence:

spectively) mainly in connection with photographic studies. There is no indication up to the present that where R is as above.

While many values of X are comprehended in this their anthelmintic properties had been investigated. 40 invention, thg most convenient y of introducing X- The especially preferred variants having 2 biphenylyl (Ex. I, and lll4)are believed to be new.

The compounds of this invention are prepared by the following route:

is in step b and it is therefore preferred to have X correspond to the X of an R'X that is a satisfactory alkylating agent. Thus when R'X is methyl or ethyl, iodide or bromide, the variants ofl having X l and Br are obl) s 9 I-COCH Br --f H3 Br 5 Z C I i 4' CH3 it' x- The anion, X, does not contribute to the parasiti cidal activity of the compounds and its identity is relatively unimportant provided it is not itself markedly toxic. Thus X- can be Cl, Br. I: SOF, MeOSO or the like.

tained directly whereas a chloride would have to be prepared from the iodide (or bromide) by a separate operation (as by exchange with silver chloride). The variants in which X is a hydrocarbyl sulfonate (especially p-toluene sulfonate or methane sulfonate) are also prepared by using the appropriate sulfonate ester as R'X in step b. Similarly methyl sulfate may be employed to give the methyl sulfate salt. In general, the iodides are extremely satisfactory and are usually preferred. The anion X" does not contribute to the parasiticidal activity of the compounds and its identity is unimportant provided it is not itself markedly toxic, thus anions of pharmaceutically acceptable acids such as Cl ,Br',l,SO.,,MeSO or the like are suitable for the purposes of this invention.

The compounds of this invention are almost com pletely insoluble in water and are rather sparingly soluble in most organic solvents. They are frequently obtained in hydrated forms from which the water of crystallization is not readily removed. The higher-melting ooQ salts are not readily recrystallized and purity is best obtained by ensuring the purity of the reactants in step c (and especially their freedom from dust and inorganic contaminants) and by extracting the product several times with organic solvents such as methanol.

The compounds of this invention can be administered to the host of the parasites in any fashion customary for such purposes as, for example, in a capsule or EXAMPLE 1 Step b Step c A solution of 25 grams (0.1M) of 2-methyl-4- biphenylyl thiazole and 22 grams of methyl iodide in 70 cc. of dimethylformamide was heated for 6-8 hours at 40 100C. Upon addition of excess ether, and cooling,

there was obtained -32 grams (75-80%) of the methiodide product. After purification by digesting with hot methanol this had a melting point of 272273C mommy;

a suspension in water or syrup or embedded in a cube Step d (30H He r Q T CH=Clta piperidine la cu OH; I

of gelatine or in a compressed tablet. Since, however, A suspension of 7.9 grams (0.02M) of the thiazole hookworms inhabit mainly the duodenum any tablet hi did d 45 grams (0 03+M) f intended to eliminate them should be such as to disintegrate rapidly after being swallowed. This would be less important if pinworms or whipworms which inhabit lower portions of the intestinal tract are the objects of treatment. Against hookworms, incorporation of the powered drug in food is often advantageous.

for about 2 hours to ensure nearly complete transformation of this insoluble reactant into the insoluble product. The product was collected, 10.5 grams (100%) from the cooled methanol and the solid was Example 1 the following variants of Formula 1 were prepared, all salts being characterized as iodides.

S washed well with methanol and with ether. After purifiz v N) Q NR cation by digestions with hot methanol and washings 2 with methanol and ether there was obtained grams l (95:70) of red crystals melting at 255256C. R I- Example Z R NR2 Yield.% M.P.. C.

4 H CH N(CH 95 238-239 5 C H CH N(C H-,,.. 80 216-218 6 C.,H CH N(CH 90 234-235 7 p-ClCJl, CH3 N(CHZ)4 95 219-220 8 pCH OC,,H., CH N(CH.) 95 216-217 9 pCH OC l-l. CH;I N(C2H 95 191-192 10 BNaphthyl CH M01 90 220-222 11 pC,,H C H CZH5 N(CH3), 90 233-235 12 pC ,-H .,C H CH3 N(C2H=,)2 95 208-209 13 -C,.H C.,H. CH N(CH2)t 90 262-263 14 c..H,.c..H. c 11. MCI-r 90 264-265 15 pClC H, CH N(C,H -,)2 90-95 190-191 16 p--BrC H CH3 N(C H-;) 90 208-209 17 p--BrC H (52H; N(CH2)4 75-85 223-225 18 pPhOC,,H CH3 N(CH;,)2 70-80 237-238 19 PPh0C H. CH N CH,)., 80-85 214-215 20 pMe0C,;. CH NrcH 85-90 279-280 H. c.,.H. 2| p-MeOC CH N(CH 85-90 280-281 H4-C,;H4

EXAMPLE 2 EXAMPLE 22 2-(p-Dimethylaminostyryl)-3methyl-4-(p- (a) 2 a i' f z g 2 11? g i I 2Methyl-4-(p-biphenylylthiazole) ethiodide 0 3 s 5 n d A mixture of 10 grams (0.04M) of 2-methyl-4-(pm0 6 y ormdml e m an biphenylyl)-thiazole, 25 cc. of dimethylformamide, and

methyl-p-toluenesulphonate (37.2 grams; 0.200 mole were mixed and heated on the steam bath at 8090C for a period of 43 hours. The solid which crystallized on cooling was filtered, washed with ether and recrystallized from isopropanol to give a product melting at about 180-l82C.

2,3-Dimethyl-4p-biphenylylthiazolium p-toluenesulphonate (26.0 grams; 0.594 mole), pdimethylaminobenzaldehyde (13.4 grams; 0.0893 mole), methanol (275 ml.) and piperidine (6.3 ml.) were mixed and heated at reflux for 19 hours. The red solid which crystallized on cooling was filtered, washed with ether and recrystallized from methanol to give a product melting at about 248254C.

EXAMPLE 3 Z-(p-Dimethylaminostyryl)-3-methyl-4-(pbiphenylyl thiazolium methylsulphate.

2-Methyl-4-biphenylylthiazole (9.0 grams; 0.036 mole), dimethylformamide (ml) and dimethylsulphate (5.0 grams; 0.040 mole) were mixed and heated on a steam bath at 8090C for a period of 18 hours. The solid which crystallized upon cooling was recrystallized from ethanol to give a product melting at about 23S-240C (decomp).

2,3-Dimethyl-4-p-phenylylthiazolium methylsulphate (4.0 grams; 0.0106 mole). pdimethylaminobenzaldehyde (2.4 grams; 0.0160 mole), methanol (50ml.) and piperidine 1.0 ml.) were mixed in the cold and then heated at reflux for 18 hours. On cooling and the addition of an excess of ether a red solid was precipitated which was filtered, washed with ether and dried at 80C to give a red-coloured solid; the product melted at about 2l0225C.

[n a further experiment. the product melted at 240-245C. By similiar operations, by the method of 10 cc. of ethyl iodide was refluxed on a steam bath for 48 hours. After cooling the mixture was diluted with 5 excess ether and gave 6.5 g. (40%) of the ethiodide.

After two recrystallizations from methanol-ether mixtures 6.5 grams of purified product was obtained which melted at 236237C.

The original dimethylformamide-ether soluble filtrates from the first crop upon evaporation to dryness gave about 10 g. more of crude seconds and/or starting material. This 10 grams of seconds was refluxed for two days longer in 25cc. of DMF with 10cc. of ethyl iodide and then gave 8.5 grams of seconds m.p. 218220C. After two recrystallizations from methanol-ether 6.6 grams of material melting at 229232C was obtained which was used for condensations.

2-(p-Pyrrolidinostyryl )-4-(p-biphenylyl) thiazole ethiodide A mixture of 4. 1 grams (0.01 M) of the thiazole ethiodide (a). 2.7 grams (0015M) of p pyrrolidinobenzaldehyde, 40 cc. of methanol and 2 cc. of piperidine was heated for 1% hour on a steam bath. The dark insoluble product had precipitated in about 5-10 minutes. After cooling the product was filtered and washed first with methanol and then with ether; yield was 5.7 grams (100%). After two or three separate digestions in cc. portions of hot methanol and after cooling, filtering and washing with methanol and with ether, 5.2 grams of the purified product was obtained which melted at 264-265C (with decomp.). The compound underwent a distinct color change at about 242-245C from dark to orangeyellow perhaps associated with the loss of ethyl iodide.

By the same procedures were prepared EXAMPLE 23 2-[p-Pyrrolidinostyr1]-3-methyl-4- p-biphenylyl thiazolium iodide, m.p., 262-263.

EXAMPLE 24 2[p-Dimethylaminostyryl]-3-methy1-4-pmethoxybiphenylyl thiazolium iodide, m.p. 28028lC.

EXAMPLE 25 2-[p-Pyrrolidinostyryl]-3-methy1-4-pmethoxybiphenylyl thiazoium iodide, m.p. 279280C.

The other compounds of this invention set forth in the general formulas IA or 1B are conveniently made using the same procedures as noted above.

Test Procedures used for Testing Compounds Against Hookworms in Dogs and Cats.

All dogs and cats received by the Laboratory are examined by the zinc sulfate flotation technic (sp. gr. 1.2) for helminths harbored. Some of those found to have hookworm infections were used in these experiments. All infections treated were natural.

Each animal to be treated was in an individual cage. Dogs were changed from Gaines meal to canned dog food for the experiment, as it is easier to find helminths in feces after canned dog food, and a dish of water was in the cage at all times. Cats were given canned cat A11 feces passed for 48 hours was checked for worms eliminated and the findings recorded. At the end of 48 hours the dogs and cats were necropsied and the worms remaining were counted and recorded. Worms, or portions thereof, found in the cecum or large intestine were considered as part of the last passed fecal speci men and recorded with the eliminated worms. The percentage of elimination was computed for each species of worm by dividing the total number of worms harbored into the number passed. Dogs treated for whipworrn infections were followed for one week and then necropsied.

The drug was weighed out and placed in capsules.

There were three (3) methods used to administer the compound orally to the dogs and cats. they were:

1. Drug placed in gelatin capsule.

2. Drug ground in mortar and placed in capsule,

3. Drug ground in mortar and mixed with food.

The results obtained are shown in the following table. Here, Col. 1, 111, V, V11 are fractions in which the numerator is the number of worms expelled and the denominator is the above number plus the number remaining at autopsy. Where a question mark is shown, the animal was known beforehand to have been infected but no wonns could be found. It is believed that in these cases the worms had been killed and had disintegrated but such results are not given full credence.

Columns 11, 1V, V1 and V111 show the percentage clearances.

food and milk before and during the experiment.

TRlALS OF THE PRODUCT OF EXAMPLE 1 1N DOGS DCSE Drug 1 11 111 IV V VI V11 V111 LEVEL administered in capsules A. caninum U. stenocephala T. canis T. leonina mg/kg (roundworms) Dog No. 873 19/19 100% 522/526 99% 5.1 874 21/22 96% 33/47 5.9 875 51/51 100% 131/132 99% 15/18 83% 7.3 883 3/21 14% 17/56 30% 5/10 50% 6.0 884 86/86 100% 163/164 100% 8.2 885 0/1 90%('?) 0/6 90%(?) 5.2 888 2/2 12/12 100% 5.6 889 116/116 100% 417/418 100% 8.2 892 36/46 83% 5.5 893 641/641 100% 9.3 896 0/8 0% 0/3 0% 7.1 898 3/30) 100% 1/1 100% 7.6 Drug ground and administered in capsules 906 86/127 67% 6.8 909 /108 97% 8.8 910 5/24 21% 5.1 91 1 405/409 99% 501/501 100% 7.6 Drug administered in food TRIALS OF THE PRODUCT 0F EXAMPLE 1 IN CATS Drug I 11 111 IV DOSE LEVEL administered in capsules A. tubaeforme T. cati mg/kg Cat. No. 565 8/9 89% 16.6 567 40/40 100% 32/32 100% 19.2 569 21/21 100% 17.9 571) H20 5% 0/1 ()71 21.7 571 20/20 100% 8.6 576 4/4 100% 27/27 100% 15.1 577 1/8 13'71 9/11 82% 25.0 579 11/11 100% 14.7 580 7/7 100% 1/1 100% 18.5 581 13/15 87% 0/2 0% 21.7

TRIALS OF THE PRODUCT OF EXAMPLE 1 IN CATS Drug 111 IV DOSE LEVEL admimstered in capsules A. tubaefomie T. cati mg/kg Drug ground and administered in capsules 589 /10 100% 20.0 Drug ground and administered in food TRlALS OF THE PRODUCT OF EXAMPLE 4.

Drug administered 1 ll [11 IV DOSE LEVEL in capsules to Dogs A, caninum T. canis mg/kg Dog No. 576 6/1 1 54.5% H1 100% 25 590 1/1 100% 25 Drug administered in capsules to Cats A. tubaeforme T. cati Cat No. 447 10/10 100% 432 5/5 100% 435 2/2 100% 11/11 100% 15 Test Procedures used for Testing Against Syphacia 0bvelata in Mice All mice received in our laboratory are naturally infected with S. obvelata.

Each mouse is placed in a separate small cage, which contains a feeding rack (designed so that food scraps do not fall through the wire mesh bottom of the cage) and a water bottle, and beneath the cage is a pan of water to catch feces and worms. Two or three cages make up a single experiment.

Each mouse is weighed, the desired amount of drug (as an emulsion made by grinding in a mortar with Tween 80 and water) is drawn up into a syringe, the blunt needle inserted into the esophagus, and the drug released into the stomach.

At the end of 24 hours the pan is removed from beneath the cage and a new pan of water substituted. The material in the removed pan is searched for worms and The results obtained are shown in the following table. Here Col. 1 is the experiment number, Column 11 are fractions in which the numerator is the number of wonns expelled and the denominator is the above number plus the number remaining at autopsy and C01. 111

is the percentage clearance.

TRIALS OF THE PRODUCT OF EXAMPLE 14 IN MICE.

Dose level: Mice No, Col. 1 Col. [1 C01. 111

1 (17-A-29 84/84 2 35/37 94.7% Avg. 97.4%

Smg/kg.

3 67 A-30 103/103 100% 4 17/17 100% Avg. 100% 5 4/4 100% b 67 A-38 H4 25% 7 43/44 97.8% Avg. 40.9% 8 0/7 0% 9 b7 A-39 34/43 79% 10 25/25 100% Avg 91.4% 1 1 20/21 95.3%

IOmg/kg. 12 67 A-33 63/63 100% 13 118/118 100% Avg. 100% 14 12/12 100% 15 7 A-34 5/5 100% 16 5/5 100% Avg. 10091 1 7 40/40 100% 18 67 A40 40/40 100% 19 43/44 97% Avg. 99.3% 20 16/161 100% TRIALS OF THE PRODUCT OF EXAMPLE [4 IN MICE-Continued Dose level: Mice No. Col. 1 Col. ll Col. lll

2| 6'! A-4l 3/9 33.3% 22 17 17 100% Av 66.7%

23 68 A450 45/45 100% 24 43/43 100% Avg. 100% 25 14/14 100% ZUmg/kg. 66 A-319 48/48 100% 164/164 100% Avg. 113/113 100% 62/62 100% Avg. 00% 80/80 100% 19/19 100% Avg. 00% 21 21 100% 200mg/kg. 66 A-307 393/393 l00% 76/76 100% Avg. 00% 246/246 100% We claim: where Y is selected from the group consisting of lower 1. A nematocidal composition which contains a nematocidally effective amount of a compound of the formula alkoxy and hydrogen, wherein R is lower alkyl and where X is an anion of a pharmaceutically acceptable acid and a carrier therefore suitable for oral administration.

where Y is hydrogen, where R is methyl and where X- is an anion of a pharmaceutically acceptable acid and a carrier therefor suitable for oral administration.

2. The composition of claim 1 in which X is selected from the group consisting of Cl, Br, 1, S0 and Met)- S0 3. The composition of claim 1 where X is l.

4. The composition of claim 1 in which the carrier is a capsule, tablet, syrup or food.

5. The composition of claim 4 in which the carrier is a capsule or tablet.

6. The composition of claim 2 in which the carrier is a capsule, tablet, syrup or food.

7. The composition of claim 6 in which the carrier is a capsule or tablet.

8. A nematocidal composition which contains a nematocidally effective amount of a compound of the formula 9. The composition of claim 8 in which the carrier is a capsule, tablet, syrup or food.

10. The composition of claim 8 in which X is Cl, Br, 1, S0, or MeOSO 11. The composition of claim 10 in which the carrier is a capsule, tablet, syrup or food.

12. The composition of claim 8 where R is ethyl, and Y is hydrogen.

13. The composition according to claim 12 in which X is I.

14. The composition of claim 12 in which X" is Cl, B I, S0,, or MeOSO 15. The composition of claim 12 in which the carrier is a capsule, tablet, syrup or food.

16. The composition of claim 13 in which the carrier is a capsule or tablet.

17. The method of eliminating parasitic nematodes infesting the intenstinal tract of a mammal which comwhere Y is selected from the group consisting of hydrogen and lower alkoxy, where R is lower alkyl, and

where X is an anion of a pharmaceutically acceptable acid.

18. The method of claim 17 wherein X is selected from the group consisting of Cl, 8,, l, S and MeO- S0 19. The method claim 18 in which the amount of compound administered is to 25 mg. of cation per kg. of mammal bodyweight.

20. The method of claim 17 where the nematodes are hookworms.

21. The method of claim 17 where the mammal is a dog.

22. The method of claim 21 in which the nematodes are hookworms.

23. The method of claim 22 in which the amount of compound administered is 5 to 25 mg/kg cation/kg of mammal bodyweight.

24. The method of claim 21 in which the amount of compound administered is 5 to 25 mg. of cation per kgv of mammal bodyweight.

25. The method of claim 21 wherein X is selected from the group consisting of Cl. B 1, S0 and MeO- S0 26. The method of claim 25 in which the nematodes are hookworms.

27. The method of claim 26 in which the amount of compound administered is 5 to 25 mg. of cation per kg.

. of mammal bodyweight.

28. The method of claim wherin the compound is administered in an amount of 5 to mg/kg cation of animal bodyweight.

29. The method of claim 20 wherein X is selected from the group consisting of Cl, 8,, I, SO. and MeO- S0 30. The method of eliminating parasitic nematodes infesting the intestinal tract of a mammal which comprises orally administering to said mammal a nematocidally effective amount of a compound of the formula where X is an anion of a pharmaceutically acceptable acid.

31. The method of claim 30 in which the compound is administered in the amount of 5 to 25 mg. of cation per kg. of mammal bodyweight.

32. The method of claim 31 in which X' is selected from the group consisting of Cl, B,., I, SO.,, and MeO- S0 33. The method of claim 32 in which the nematodes are pinworms.

34. The method of claim 30 wherein the nematodes are pinworms.

35. The method of claim 34 in which the compound is administered in the amount of 5 to 25 mg. of cation per kg. of mammal bodyweight.

36. The method of claim 30 in which X is selected from the group consisting of Cl, B I, SO.,, and MeO- S0 37. The method of claim 36 in which the nematodes are pinworms.

38. The method of claim 30 wherein Y is hydrogen and R is ethyl.

39. The method of claim 38 in which X is selected from the group consisting of Cl, B I, S0 and Me()- S0 40. The method of claim 39 in which the compound is administered in the amount of 5 to 25 mg. of cation per kg. of mammal bodyweight.

41. The method of claim 38 in which the nematodes are pinworms.

42. The method of claim 41 in which X is selected from the group consisting of Cl, B 1, S0 and MeO- S0 43. The method of claim 42 in which the compound is administered in the amount of 5 to 25 mg. of cation per kg. of mammal bodyweight. 

1. A NEMATOCIDAL COMPOSITION WHICH CONTAINS A NEMATOCIDALLY EFFECTIVE AMOUNT OF A COMPOUND OF THE FORMULA
 2. The composition of claim 1 in which X is selected from the group consisting of Cl, Br, I, SO4 and MeOSO3.
 3. The composition of Claim 1 where X is I .
 4. The composition of claim 1 in which the carrier is a capsule, tablet, syrup or food.
 5. The composition of claim 4 in which the carrier is a capsule or tablet.
 6. The composition of claim 2 in which the carrier is a capsule, tablet, syrup or food.
 7. The composition of claim 6 in which the carrier is a capsule or tablet.
 8. A NEMATOCIDAL COMPOSITION WHICH CONTAINS A NEMATOCIDALLY EFFECTIVE AMOUNT OF A COMPOUND OF THE FORMULA
 9. The composition of claim 8 in which the carrier is a capsule, tablet, syrup or food.
 10. The composition of claim 8 in which X is Cl, Br, I, SO4 or MeOSO3.
 11. The composition of claim 10 in which the carrier is a capsule, tablet, syrup or food.
 12. The composition of claim 8 where R'' is ethyl, and Y is hydrogen.
 13. The composition according to claim 12 in which X is I.
 14. The composition of claim 12 in which X is Cl, Br, I, SO4 or MeOSO3.
 15. The composition of claim 12 in which the carrier is a capsule, tablet, syrup or food.
 16. The composition of claim 13 in which the carrier is a capsule or tablet.
 17. The method of eliminating parasitic nematodes infesting the intenstinal tract of a mammal which comprises orally administering to said mammal a nematocidally effective amount of the compound
 18. The method of claim 17 wherein X is selected from the group consisting of Cl, Br, I, SO4, and MeOSO3.
 19. The method claim 18 in which the amount of compound administered is 5 to 25 mg. of cation per kg. of mammal bodyweight.
 20. The method of claim 17 where the nematodes are hookworms.
 21. The method of claim 17 where the mammal is a dog.
 22. The method of claim 21 in which the nematodes are hookworms.
 23. The method of claim 22 in which the amount of compound administered is 5 to 25 mg/kg cation/kg of mammal bodyweight.
 24. The method of claim 21 in which the amount of compound administered is 5 to 25 mg. of cation per kg. of mammal bodyweight.
 25. The method of claim 21 wherein X is selected from the group consisting of Cl, Br, I, SO4 and MeOSO3.
 26. The method of claim 25 in which the nematodes are hookworms.
 27. The method of claim 26 in which the amount of compound administered is 5 to 25 mg. of cation per kg. of mammal bodyweight.
 28. The method of claim 20 wherin the compound is administered in an amount of 5 to 25 mg/kg cation of animal bodyweight.
 29. The method of claim 20 wherein X is selected from the group consisting of Cl, Br, I, SO4 and MeOSO3.
 30. The method of eliminating parasitic nematodes infesting the intestinal tract of a mammal which comprises orally administering to said mammal a nematocidally effective amount of a compound of the formula
 31. The method of claim 30 in which the compound is administered in the amount of 5 to 25 mg. of cation per kg. of mammal bodyweight.
 32. The method of claim 31 in which X is selected from the group consisting of Cl, Br, I, SO4, and MeOSO3.
 33. The method of claim 32 in which the nematodes are pinworms.
 34. The method of claim 30 wherein the nematodes are pinworms.
 35. The method of claim 34 in which the compound is admiNistered in the amount of 5 to 25 mg. of cation per kg. of mammal bodyweight.
 36. The method of claim 30 in which X is selected from the group consisting of Cl, Br, I, SO4, and MeOSO3.
 37. The method of claim 36 in which the nematodes are pinworms.
 38. The method of claim 30 wherein Y is hydrogen and R'' is ethyl.
 39. The method of claim 38 in which X is selected from the group consisting of Cl, Br, I, SO4 and MeOSO3.
 40. The method of claim 39 in which the compound is administered in the amount of 5 to 25 mg. of cation per kg. of mammal bodyweight.
 41. The method of claim 38 in which the nematodes are pinworms.
 42. The method of claim 41 in which X is selected from the group consisting of Cl, Br, I, SO4 and MeOSO3.
 43. The method of claim 42 in which the compound is administered in the amount of 5 to 25 mg. of cation per kg. of mammal bodyweight. 